scholarly journals An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2410 ◽  
Author(s):  
Xianwei Wang ◽  
Xiao He
Keyword(s):  
Electric Field ◽  
Ab Initio ◽  
Active Site ◽  
Md Simulation ◽  
Stark Effect ◽  
Computational Simulation ◽  
Ketosteroid Isomerase ◽  
Correlation Relationship ◽  
Amber Force Field ◽  
Electrostatic Contribution

The electric field in the hydrogen-bond network of the active site of ketosteroid isomerase (KSI) has been experimentally measured using vibrational Stark effect (VSE) spectroscopy, and utilized to study the electrostatic contribution to catalysis. A large gap was found in the electric field between the computational simulation based on the Amber force field and the experimental measurement. In this work, quantum mechanical (QM) calculations of the electric field were performed using an ab initio QM/MM molecular dynamics (MD) simulation and electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method. Our results demonstrate that the QM-derived electric field based on the snapshots from QM/MM MD simulation could give quantitative agreement with the experiment. The accurate calculation of the electric field inside the protein requires both the rigorous sampling of configurations, and a QM description of the electrostatic field. Based on the direct QM calculation of the electric field, we theoretically confirmed that there is a linear correlation relationship between the activation free energy and the electric field in the active site of wild-type KSI and its mutants (namely, D103N, Y16S, and D103L). Our study presents a computational protocol for the accurate simulation of the electric field in the active site of the protein, and provides a theoretical foundation that supports the link between electric fields and enzyme catalysis.

scholarly journals A Preorganized Electric Field Leads to Minimal Geometrical Reorientation in the Catalytic Reaction of Ketosteroid Isomerase

2020 ◽  
Author(s):  
Yufan Wu ◽  
Stephen Fried ◽  
Steven Boxer
Keyword(s):  
Electric Field ◽  
Electric Fields ◽  
Ground State ◽  
Active Site ◽  
Electrostatic Interactions ◽  
Stark Effect ◽  
Structural Changes ◽  
Enzymatic Catalysis ◽  
Ketosteroid Isomerase ◽  
Computational Enzyme Design

<div><p>Electrostatic interactions play a pivotal role in enzymatic catalysis and are increasingly modeled explicitly in computational enzyme design; nevertheless, they are challenging to measure experimentally. Using vibrational Stark effect (VSE) spectroscopy, we have measured electric fields inside the active site of the enzyme ketosteroid isomerase (KSI). These studies have shown that these fields can be unusually large, but it has been unclear to what extent they specifically stabilize the transition state (TS) relative to a ground state (GS). In the following, we use crystallography and computational modeling to show that KSI’s intrinsic electric field is nearly perfectly oriented to stabilize the geometry of its reaction’s TS. Moreover, we find that this electric field adjusts the orientation of its substrate in the ground state so that the substrate needs to only undergo minimal structural changes upon activation to its TS. This work provides evidence that the active site electric field in KSI is preorganized to facilitate catalysis and provides a template for how electrostatic preorganization can be measured in enzymatic systems. <br></p></div>

scholarly journals Extreme electric fields power catalysis in the active site of ketosteroid isomerase

Science ◽  
2014 ◽  
Vol 346 (6216) ◽  
pp. 1510-1514 ◽  
Author(s):  
Stephen D. Fried ◽  
Sayan Bagchi ◽  
Steven G. Boxer
Keyword(s):  
Electric Field ◽  
Electric Fields ◽  
Active Site ◽  
Stark Effect ◽  
Catalytic Effect ◽  
Biomolecular Systems ◽  
Ketosteroid Isomerase ◽  
Rate Determining Step ◽  
Experimental Approaches ◽  
A Charge

Enzymes use protein architecture to impose specific electrostatic fields onto their bound substrates, but the magnitude and catalytic effect of these electric fields have proven difficult to quantify with standard experimental approaches. Using vibrational Stark effect spectroscopy, we found that the active site of the enzyme ketosteroid isomerase (KSI) exerts an extremely large electric field onto the C=O chemical bond that undergoes a charge rearrangement in KSI’s rate-determining step. Moreover, we found that the magnitude of the electric field exerted by the active site strongly correlates with the enzyme’s catalytic rate enhancement, enabling us to quantify the fraction of the catalytic effect that is electrostatic in origin. The measurements described here may help explain the role of electrostatics in many other enzymes and biomolecular systems.

scholarly journals A Preorganized Electric Field Leads to Minimal Geometrical Reorientation in the Catalytic Reaction of Ketosteroid Isomerase

2020 ◽  
Author(s):  
Yufan Wu ◽  
Stephen Fried ◽  
Steven Boxer
Keyword(s):  
Electric Field ◽  
Electric Fields ◽  
Ground State ◽  
Active Site ◽  
Electrostatic Interactions ◽  
Stark Effect ◽  
Structural Changes ◽  
Enzymatic Catalysis ◽  
Ketosteroid Isomerase ◽  
Computational Enzyme Design

<div><p>Electrostatic interactions play a pivotal role in enzymatic catalysis and are increasingly modeled explicitly in computational enzyme design; nevertheless, they are challenging to measure experimentally. Using vibrational Stark effect (VSE) spectroscopy, we have measured electric fields inside the active site of the enzyme ketosteroid isomerase (KSI). These studies have shown that these fields can be unusually large, but it has been unclear to what extent they specifically stabilize the transition state (TS) relative to a ground state (GS). In the following, we use crystallography and computational modeling to show that KSI’s intrinsic electric field is nearly perfectly oriented to stabilize the geometry of its reaction’s TS. Moreover, we find that this electric field adjusts the orientation of its substrate in the ground state so that the substrate needs to only undergo minimal structural changes upon activation to its TS. This work provides evidence that the active site electric field in KSI is preorganized to facilitate catalysis and provides a template for how electrostatic preorganization can be measured in enzymatic systems. <br></p></div>

scholarly journals Quantitative, directional measurement of electric field heterogeneity in the active site of ketosteroid isomerase

2012 ◽  
Vol 109 (6) ◽  
pp. E299-E308 ◽  
Author(s):  
A. T. Fafarman ◽  
P. A. Sigala ◽  
J. P. Schwans ◽  
T. D. Fenn ◽  
D. Herschlag ◽  
...  
Keyword(s):  
Electric Field ◽  
Active Site ◽  
Ketosteroid Isomerase ◽  
Field Heterogeneity

scholarly journals Electric field orientations in solution and enzyme active site revealed by a two-directional vibrational probe

2021 ◽  
Author(s):  
Chu Zheng ◽  
Yuezhi Mao ◽  
Jacek Kozuch ◽  
Austin Atsango ◽  
Zhe Ji ◽  
...  
Keyword(s):  
Electric Field ◽  
Active Site ◽  
Stark Effect ◽  
Direct Evidence ◽  
Chemical Species ◽  
Fundamental Difference ◽  
Field Orientation ◽  
Enzyme Active Site ◽  
Liver Alcohol Dehydrogenase ◽  
Catalytic Power

The catalytic power of an electric field depends on its magnitude and orientation with respect to the reactive chemical species. Understanding and designing new catalysts for electrostatic catalysis thus requires methods to measure the electric field orientation and magnitude at the molecular scale. We demonstrate that electric field orientations can be extracted using a two-directional vibrational probe by exploiting the vibrational Stark effect of both the C=O and C-D stretches of a deuterated aldehyde. Combining spectroscopy with molecular dynamics and electronic structure partitioning methods, we demonstrate that despite distinct polarities, solvents act similarly in their preference for electrostatically stabilizing large bond dipoles at the expense of destabilizing small ones. In contrast, we find that for an active site aldehyde inhibitor of liver alcohol dehydrogenase, the electric field orientation deviates markedly from that found in solvents, providing direct evidence for the fundamental difference between the electrostatic environments of solvents and a preorganized enzyme active site.

scholarly journals Mass spectrometric studies of a modified active-site tetrapeptide from delta 5-3-ketosteroid isomerase of Pseudomonas testosteroni.

1982 ◽  
Vol 257 (21) ◽  
pp. 12589-12593
Author(s):  
T M Penning ◽  
D N Heller ◽  
T M Balasubramanian ◽  
C C Fenselau ◽  
P Talalay
Keyword(s):  
Active Site ◽  
Mass Spectrometric ◽  
Ketosteroid Isomerase ◽  
Pseudomonas Testosteroni

Spontaneous electric polarization and electric field gradient in hybrid improper ferroelectrics: insights and correlations

2021 ◽  
Author(s):  
Samuel Silva dos Santos ◽  
Michel L. Marcondes ◽  
Ivan P. Miranda ◽  
Pedro Rocha-Rodrigues ◽  
Lucy Vitória Credidio Assali ◽  
...  
Keyword(s):  
Electric Field ◽  
Electric Field Gradient ◽  
Ab Initio ◽  
Field Gradient ◽  
Electric Polarization ◽  
Double Perovskites

An ab-initio study for several hybrid improper ferroelectric (HIF) materials in the Ruddlesden-Popper phases and double perovskites structures is here presented. The focus is on the correlation between the electric...

scholarly journals Globally Optimized Molecular Embeddings for Dynamic Reaction Solvate Shell Optimization and Active Site Design

2021 ◽  
Author(s):  
Dominik M. Behrens ◽  
Bernd Hartke
Keyword(s):  
Global Optimization ◽  
Active Site ◽  
Solvate Shell ◽  
Dynamic Reaction ◽  
Ketosteroid Isomerase ◽  
Recent Interest ◽  
Site Design ◽  
Shell Optimization

AbstractWe demonstrate how a full QM/MM derivatization of the recently developed GOCAT model can be utilized in the global optimization of molecular embeddings. To this end, we provide two distinct examples: An $$\text {S}_\text {N}2$$ S N 2 reaction, and one enzymatic example of recent interest, the ketosteroid isomerase. These serve us to highlight the advantages of such an approach and sketch the roadmap for further improvements.

The giant Stark effect in armchair-edge phosphorene nanoribbons under a transverse electric field

2018 ◽  
Vol 382 (4) ◽  
pp. 193-198 ◽  
Author(s):  
Benliang Zhou ◽  
Benhu Zhou ◽  
Pu Liu ◽  
Guanghui Zhou
Keyword(s):  
Electric Field ◽  
Stark Effect ◽  
Transverse Electric ◽  
Transverse Electric Field
Sign in / Sign up

Export Citation Format

Share Document